8/18/2019 BIO 103 Lecture 11

1/12

!"#$"%&

%

1

QUIZ #5

15 minutes

Please write your name on the quiz

Please write your section on the quiz

2

LECTURE 11

Image by Gopal Murti/Visuals Unlimited, Inc.

When Development goes wrong: Cancer

Learning Goals

• 

Recognize that cancer is a disease caused by our own genes

•  Understand how scientists discovered the causes of cancer

• 

Recognize the difference between oncogenes and tumorsuppressors

•   Appreciate the action of carcinogens in mutating or rearranging

the DNA

• 

See the link between developmental genes and cancer genes

3

The relationship between apoptosis and disease

4

8/18/2019 BIO 103 Lecture 11

2/12

!"#$"%&

(

5

The main causes of death in the U.S.

What are some of the differences now as comparedto ~100 years ago?

6

7

Cancer is the uncontrolled proliferation/

division of cells or loss of cell death

• 

Cancer is a collection

of diseases.

 –  Leukemias

 – 

Sarcomas –

 

Carcinomas 

• 

Cancer cells form large

masses of themselves,

tumors.

Lung squamous cell carcinoma

Blood from chronic myelogenous leukemia

Normal blood

8

Cancer is caused by genetic changes to our cells

8/18/2019 BIO 103 Lecture 11

3/12

!"#$"%&

#

9

Photos: G. Steven Martin

Normal cells can become transformed  

Normal cells exhibiting

contact inhibitionTransformed cells

10

Cancer is caused by changes to our genes

carcinogen

11

47,000 mutations found in a lung cancer

Govindan, et al. (2012) Cell  150: 1121-1134.12

DNA damage causes cancer by mutating the

genes that control cell division and survival

Somatic mutations: Mutation occurs in cells of the body.

Germ line mutations: Mutation occurs in the germ cells.

Oncogenes are required for celldivision (gas)

Tumor Suppressors are required tostop cell division (brakes)

stop undergoing mitosis ose ability to undergo contact inhibition

Proto-oncogenes

8/18/2019 BIO 103 Lecture 11

4/12

!"#$"%&

&

13

Breakthrough in our understanding of

cancer came from studying viruses

Human cancer-causing viruses

14

HPV-associated cervical cancer

killed Henrietta Lacks (HeLa)

15

16

Rous Sarcoma Virus

Rous P.. (1911) A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med.13:397

How do you think he proved it was a virus?

8/18/2019 BIO 103 Lecture 11

5/12

!"#$"%&

)

17

Rous sarcoma virus contains 4 genes

18

19

Two ways viruses

cause tumors

1. 

Incorporates a proto-oncogene into its viral

genome.

2. Insert next to proto-oncogene

in host DNA.

© NaturePublishing Group1976

20

RAS was the first known mutated

human oncogene

8/18/2019 BIO 103 Lecture 11

6/12

!"#$"%&

*

21

RAS pathway

22

•  HRAS

•  NRAS

•  KRAS

Humans and mice have 3 RAS genes

-   All can be mutated to a gain-of-function via missense mutation at GLY12.

-  This renders the GTPase domain of Ras insensitive to inactivation,

locking the protein in an active, GTP-bound "on state".

23

KRAS gain of function (activated RAS) is

sufficient to cause cancer in a mouse

Parikh N et al. Mol Cancer Res 2012;10:845-855

24

KRAS is an essential gene

!Comparison of Kras "/" embryos and control littermates.

8/18/2019 BIO 103 Lecture 11

7/12

!"#$"%&

+

25

The normal function of proto-oncogenes is

to control cell growth and proliferation.

Famous oncogenesERB

RAS

SRC

 ABL

BCL2MYC

26

Some

chromosomal

translocationsmove a gene

upstream of

another gene’s

enhancer element

In Burkitt lymphoma, Myc, which is

normally found on chromosome 8,

is transferred to chromosome 14.

This is known as a chromosome

translocation; such changes can be

characteristic of particular cancers.

27

Chromosome abnormalities in cancer cells

Chromosome painting (spectral karyotyping) reveals multipletranslocations in this promyelocytic leukemia patient

Normal PML 28

Tumor suppressors

•  “Checkpoints” prevent inappropriate proliferation.

•  Disruption of both copies of a tumor suppressor leads to

cancer

•  In contrast, only one allele of an oncogene needs to be

activated.

Rb

8/18/2019 BIO 103 Lecture 11

8/12

!"#$"%&

,

29

Retinoblastoma : Knudson's hypothesis

Sporadic Familial

Late onset Early onsetSingle tumor Multiple Tumors

Limited Secondary Tumors

Inherit two normal genes Inherit one normal/one defective

Lose one - a rare event Lose normal one

Lose other Tumor

Tumor  

30

Knudson’s two hit hypothesis

31

Famous tumor suppressors

•  Rb and P53 are the most frequently mutated genes in human

cancers.

•  P53 encodes the p53 protein that responds to DNA damage.

Upon sensing DNA damage, p53 is activated, resulting ineither G1 cell cycle arrest or apoptosis.

• 

PTEN  encodes a phosphatase that inhibits kinase signaling.

•  BRCA1 and BRCA2  encode DNA binding proteins requiredfor DNA damage repair.

32

Tumor suppressors come in many different flavors

8/18/2019 BIO 103 Lecture 11

9/12

!"#$"%&

!

33

Loss of APC  

 Activation of ras 

Loss of DCC  

Loss of p53 

Other mutations 

Other mutations 

Cancer is a multistep process

34

Metastasis

35

 Angiogenesis

36

Endostatin, an angiogenesis inhibitor can

cure certain solid cancers

8/18/2019 BIO 103 Lecture 11

10/12

!"#$"%&

%$

37

Why has cancer been so tough to eradicate

• 

Cancer is a disease of our own cells and genes that have

become altered in some way.

• 

Because these cells look and behave like our cells, there is no

plethora of foreign antigens for our immune system to

recognize.

• 

Drugs that kill tumor cells also kill our normal cells.

•  There are hundreds of different cancers.

38

Treating

Cancer

Diseases

39

Targeted therapies based on

personalized medicine

40

Key concepts

•  Cancer is a disease of our own genes and cells.

•  Carcinogens are compounds that cause cancer by mutatingour genes.

• 

Proto-oncogenes normally promote cell division and getactivated to act as oncogenes in cancer.

•  Tumor suppressor genes normally act to prevent cell division.

Both copies are lost/deleted in cancer.

• 

Cancer usually requires activation of oncogenes and loss of

tumor suppressors in the same cell.

8/18/2019 BIO 103 Lecture 11

11/12

!"#$"%&

%%

41

Class exercise on breast

cancer susceptibility

•  Inherited breast cancer susceptibility (BRCA)

•  Women who inherit a mutant BRCA1 gene

have a 66% chance of breast cancer or

ovarian cancer by age 55.

42

Is susceptibility dominant orrecessive?

Penetrance:

Expressivity:

43

From Biology: How Life Works

BRCA1 associated cancers: Usually inheritance of a mutant copyand then subsequent deletion/mutation of the remaining copy.

What’s the resemblance to the Knudson’s retinoblastoma example?44

BRCA1 mutations

8/18/2019 BIO 103 Lecture 11

12/12

!"#$"%&

%(

45

Hypothetical BRCA1 family

Why no BRCA1 mutant homozygotes?Why do some daughters carry the mutant BRCA1 but not get

affected?

Why do some daughters not carrying the mutant BRCA1 still get

affected?

From Biology: How Life Works

46

BRCA1 and BRCA2  are both

essential genes

Brca2 +/+ Brca2 -/-

Brca1 +/+ Brca1 -/-

The Brca1 and Brca2  loss of function mutant phenotype is almost identical.

What does that say about the normal function of these 2 genes?

47

BRCA1 and BRCA2 proteins act in a

complex to repair damaged DNA

48

Key concepts

•  Cancer is a disease of our own genes and cells.

•  Carcinogens are compounds that cause cancer by mutatingour genes.

• 

Proto-oncogenes normally promote cell division and getactivated to act as oncogenes in cancer.

•  Tumor suppressor genes normally act to prevent cell division,

or repair DNA damage. Both copies are lost/deleted in cancer.

• 

Cancer usually requires activation of oncogenes and loss of

tumor suppressors in the same cell.